tbuckley/cabot-search huggingface dataset:
Origin and Evolution of Nitrogen Fixation in Prokaryotes
Authors: Hong-Wei Pi, Jinn-Jy Lin, Chi-An Chen, Po-Hsiang Wang, Yin-Ru Chiang, Chieh-Chen Huang, Chiu-Chung Young, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2022)

Abstract The origin of nitrogen fixation is an important issue in evolutionary biology. While nitrogen is required by all living organisms, only a small fraction of bacteria and archaea can fix nitrogen. The prevailing view is that nitrogen fixation first evolved in archaea and was later transferred to bacteria. However, nitrogen-fixing (Nif) bacteria are far larger in number and far more diverse in ecological niches than Nif archaea. We, therefore, propose the bacteria-first hypothesis, which postulates that nitrogen fixation first evolved in bacteria and was later transferred to archaea. As &amp;gt;30,000 prokaryotic genomes have been sequenced, we conduct an in-depth comparison of the two hypotheses. We first identify the six genes involved in nitrogen fixation in all sequenced prokaryotic genomes and then reconstruct phylogenetic trees using the six Nif proteins individually or in combination. In each of these trees, the earliest lineages are bacterial Nif protein sequences and in the oldest clade (group) the archaeal sequences are all nested inside bacterial sequences, suggesting that the Nif proteins first evolved in bacteria. The bacteria-first hypothesis is further supported by the observation that the majority of Nif archaea carry the major bacterial Mo (molybdenum) transporter (ModABC) rather than the archaeal Mo transporter (WtpABC). Moreover, in our phylogeny of all available ModA and WtpA protein sequences, the earliest lineages are bacterial sequences while archaeal sequences are nested inside bacterial sequences. Furthermore, the bacteria-first hypothesis is supported by available isotopic data. In conclusion, our study strongly supports the bacteria-first hypothesis.
Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence
Authors: Federico Zacchini, Giulia Venturi, Veronica De Sanctis, Roberto Bertorelli, Claudio Ceccarelli, Donatella Santini, Mario Taffurelli, Marianna Penzo, Davide Treré, Alberto Inga, Erik Dassi, Lorenzo Montanaro
Journal: Genome biology (2022)

Abstract Background Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. In humans, its defective function is associated with cancer development and induces specific post-transcriptional alterations of gene expression. In this study, we seek to unbiasedly identify mRNAs regulated by dyskerin in human breast cancer-derived cells. Results We find that dyskerin depletion affects the expression and the association with polysomes of selected mRNA isoforms characterized by the retention of H/ACA box snoRNA-containing introns. These snoRNA retaining transcripts (snoRTs) are bound by dyskerin in the cytoplasm in the form of shorter 3′ snoRT fragments. We then characterize the whole cytoplasmic dyskerin RNA interactome and find both H/ACA box snoRTs and protein-coding transcripts which may be targeted by the snoRTs’ guide properties. Since a fraction of these protein-coding transcripts is involved in the nuclear hormone receptor binding, we test to see if this specific activity is affected by dyskerin. Obtained results indicate that dyskerin dysregulation may alter the dependence on nuclear hormone receptor ligands in breast cancer cells. These results are paralleled by consistent observations on the outcome of primary breast cancer patients stratified according to their tumor hormonal status. Accordingly, experiments in nude mice show that the reduction of dyskerin levels in estrogen-dependent cells favors xenograft development in the absence of estrogen supplementation. Conclusions Our work suggests a cytoplasmic function for dyskerin which could affect mRNA post-transcriptional networks relevant for nuclear hormone receptor functions.
Fibroblast growth factor receptor 1/Klothoβ agonist BFKB8488A improves lipids and liver health markers in patients with diabetes or NAFLD: A phase 1b randomized trial
Authors: Chin Wong, Ajit Dash, Jill Fredrickson, Nicholas Lewin‐Koh, Shan Chen, Kenta Yoshida, Yanqiu Liu, Johnny Gutierrez, Rebecca Kunder
Journal: Hepatology (2022)

Background and Aims: BFKB8488A is a bispecific antibody targeting fibroblast growth factor receptor 1c and Klothoβ. This phase 1b study assessed safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of BFKB8488A in patients with type 2 diabetes mellitus (T2DM) or NAFLD. Approach and Results: Patients were randomized to receive multiple doses of BFKB8488A at various dose levels and dosing intervals (weekly, every 2 weeks, or every 4 weeks) or placebo for 12 weeks. The primary outcome was the safety of BFKB8488A. Overall, 153 patients (T2DM: 91; NAFLD: 62) were enrolled and received at least one dose of treatment. Of these, 102 patients (62.7%) reported at least one adverse event (BFKB8488A: 83 [68.6%]; placebo: 19 [59.4%]). BFKB8488A exhibited nonlinear pharmacokinetics, with greater than dose‐proportional increases in exposure. The treatment‐emergent antidrug antibody incidence was 22.7%. Overall, trends in exposure‐dependent increases in high‐density lipoprotein (HDL) and decreases in triglyceride levels were observed. Decreases in alanine aminotransferase and aspartate aminotransferase were 0.7% and 9.2% for medium exposure and 7.3% and 11.2% for high‐exposure tertiles, compared with increases of 7.5% and 17% in the placebo group, respectively, at Day 85. In patients with NAFLD, the mean decrease from baseline liver fat was 13.0%, 34.5%, and 49.0% in the low‐, medium‐, and high‐exposure tertiles, respectively, compared with 0.1% with placebo at Day 85. Conclusions: BFKB8488A was adequately tolerated in patients with T2DM or NAFLD, leading to triglyceride reduction, HDL improvements, and trends in improvement in markers of liver health for both populations and marked liver fat reduction in patients with NAFLD. (ClinicalTrials.gov: NCT03060538).
SGLT-2 inhibition by empagliflozin has no effect on experimental arterial thrombosis in a murine model of low-grade inflammation
Authors: Luca Liberale, Simon Kraler, Yustina M Puspitasari, Nicole R Bonetti, Alexander Akhmedov, Stefano Ministrini, Fabrizio Montecucco, Nikolaus Marx, Michael Lehrke, Niels-Ulrik K Hartmann, Jürg H Beer, Florian A Wenzl, Francesco Paneni, Thomas F Lüscher, Giovanni G Camici
Journal: Cardiovascular Research (2022)

Abstract Aims Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular (CV) disease (ASCVD). Selective sodium–glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of its glucose lowering effects. Yet, its mechanism of action remains largely undetermined. Here, we aimed to test whether empagliflozin affects arterial thrombus formation in baseline (BSL) conditions or low-grade inflammatory states, a systemic milieu shared among patients with ASCVD. Methods and results Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg body weight) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg body weight), before carotid thrombosis was induced by photochemical injury. The between-group difference in Doppler-flow probe detected time-to-occlusion remained within the predefined equivalence margin (Δ = |10.50|), irrespective of low-grade inflammation (95% confidence interval, –9.82 to 8.85 and –9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmoL/L, respectively. Ex vivo platelet aggregometry suggested similar activation status, corroborated by unchanged circulating platelet-factor 4 plasma levels. In concert, carotid PAI-1 expression and tissue factor (TF) activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma D-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity. In human aortic endothelial cells pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression. Accordingly, among patients with established ASCVD or at high CV risk randomized to a daily dose of 10 mg empagliflozin signatures of thrombotic (i.e. TF) and fibrinolytic activity (i.e. PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up. Conclusion SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under BSL conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating arterial thrombosis.
Comparative transcriptome in large-scale human and cattle populations
Authors: Yuelin Yao, Shuli Liu, Charley Xia, Yahui Gao, Zhangyuan Pan, Oriol Canela-Xandri, Ava Khamseh, Konrad Rawlik, Sheng Wang, Bingjie Li, Yi Zhang, Erola Pairo-Castineira, Kenton D’Mellow, Xiujin Li, Ze Yan, Cong-jun Li, Ying Yu, Shengli Zhang, Li Ma, John B. Cole, Pablo J. Ross, Huaijun Zhou, Chris Haley, George E. Liu, Lingzhao Fang, Albert Tenesa
Journal: Genome biology (2022)

Abstract Background Cross-species comparison of transcriptomes is important for elucidating evolutionary molecular mechanisms underpinning phenotypic variation between and within species, yet to date it has been essentially limited to model organisms with relatively small sample sizes. Results Here, we systematically analyze and compare 10,830 and 4866 publicly available RNA-seq samples in humans and cattle, respectively, representing 20 common tissues. Focusing on 17,315 orthologous genes, we demonstrate that mean/median gene expression, inter-individual variation of expression, expression quantitative trait loci, and gene co-expression networks are generally conserved between humans and cattle. By examining large-scale genome-wide association studies for 46 human traits (average n = 327,973) and 45 cattle traits (average n = 24,635), we reveal that the heritability of complex traits in both species is significantly more enriched in transcriptionally conserved than diverged genes across tissues. Conclusions In summary, our study provides a comprehensive comparison of transcriptomes between humans and cattle, which might help decipher the genetic and evolutionary basis of complex traits in both species.
Fatty acids produced by the gut microbiota dampen host inflammatory responses by modulating intestinal SUMOylation
Authors: Chaima Ezzine, Léa Loison, Nadine Montbrion, Christine Bôle-Feysot, Pierre Déchelotte, Moïse Coëffier, David Ribet
Journal: Gut Microbes (2022)

The gut microbiota produces a wide variety of metabolites, which interact with intestinal cells and contribute to host physiology. The effect of gut commensal bacteria on host protein SUMOylation, an essential ubiquitin-like modification involved in various intestinal functions, remains, however, unknown. Here, we show that short chain fatty acids (SCFAs) and branched chain fatty acids (BCFAs) produced by the gut microbiota increase protein SUMOylation in intestinal cells in a pH-dependent manner. We demonstrate that these metabolites inactivate intestinal deSUMOylases and promote the hyperSUMOylation of nuclear matrix-associated proteins. We further show that BCFAs inhibit the NF-κB pathway, decrease pro-inflammatory cytokine expression, and promote intestinal epithelial integrity. Together, our results reveal that fatty acids produced by gut commensal bacteria regulate intestinal physiology by modulating SUMOylation and illustrate a new mechanism of dampening of host inflammatory responses triggered by the gut microbiota.
The backstage of the Russian–Ukrainian war: refugees in urgent need of cardiovascular management
Authors: Bartlomiej Guzik, Anna Bernacik, Anna Pulka, Anna Kaczmarska, Tomasz J Guzik, Tomasz Grodzicki
Journal: Cardiovascular Research (2022)

With the onset of the Russian invasion of Ukraine on February 24, a constant inflow of refugees fleeing their homeland has occurred.By 1 May 2022, over 10 million people have been displaced in Ukraine, with over 5.8 million migrating as refugees.Approximately 55% of them migrated into Poland. 1,2his number does not include people who had crossed the borders illegally, without registration, which may account for an additional 10-20%.The dynamics of refugee inflow into Poland are presented in Figure 1.According to the UN Refugee Agency (UNHCR), women are 88% of adult refugees, and a majority of them (95.3%) is the Ukrainian nationality.The elderly account for 14%, while children account for 36%. 2 While numerous arrive with pre-existing comorbidities, their health condition is often exacerbated by the ordeal of the preceding days and weeks, unprecedented levels of stress leading to psychological challenges and depression.At the moment of arrival, at the border of the Republic of Poland, 18-30% of incoming refugees reported an urgent need for medical attention.Thus, approximately one million people urgently needed medical assistance in the last three months.In Poland alone, over 500 000 new Ukrainian patients were reported to need urgent medical aid. 1
Secondary Acute Myeloid Leukemia: Pathogenesis and Treatment
Authors: Debora Capelli, Diego Menotti, Alessandro Fiorentini, Francesco Saraceni, Attilio Olivieri
Journal: Leukemia (2022)

Secondary acute myeloid leukemia includes acute myeloid leukemia that arises either from a previous myeloid hematologic disease such as myelodysplastic syndrome, chronic myeloproliferative syndrome, or myelodysplastic/myeloproliferative overlap syndromes or from a previous chemotherapy or radiotherapy performed for another disease. Secondary acute myeloid leukemia is characterized by a worse prognosis than its de novo counterparts, with a 5-year overall survival of <30% despite an advanced insight into pathogenesis and new available treatments. The best therapeutic strategy is to achieve complete remission with a negative minimal residual disease followed by hematopoietic stem cell transplantation; however, advanced age of patients at diagnosis, multiple comorbidities, and lower rate of complete remission makes these approaches available only for a small fraction of secondary acute myeloid leukemia patients. In this chapter, we discuss the epidemiology, pathogenesis, and prognostic factors of secondary acute myeloid leukemia. Also, we discuss the main treatments currently available for eligible patients (fit patients) and non-eligible patients (unfit patients) for intensive chemotherapy and future treatment perspectives.
Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis
Authors: Sandra Torres, Cristina Ortiz, Nadine Bachtler, Wenyi Gu, Leon D. Grünewald, Nico Kraus, Robert Schierwagen, Christoph Hieber, Caroline Meier, Olaf Tyc, Maximilian Joseph Brol, Frank Erhard Uschner, Bart Nijmeijer, Christoph Welsch, Marie‐Luise Berres, Carmen Garcia‐Ruiz, Jose Carlos Fernandez‐Checa, Christian Trautwein, Thomas J. Vogl, Stefan Zeuzem, Jonel Trebicka, Sabine Klein
Journal: Hepatology (2022)

Background and Aims: Janus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo . Approach and Results: Transcriptome analyses of JAK2 in human livers and other targets of pacritinib have been shown to correlate with profibrotic factors. Although transcription of JAK2 correlated significantly with type I collagen expression and other profibrotic genes, no correlation was observed for interleukin‐1 receptor‐associated kinase and colony‐stimulating factor 1 receptor. Pacritinib decreased gene expression of fibrosis markers in mouse primary and human‐derived HSCs in vitro . Moreover, pacritinib decreased the proliferation, contraction, and migration of HSCs. C 57 BL/6J mice received ethanol in drinking water (16%) or Western diet in combination with carbon tetrachloride intoxication for 7 weeks to induce alcoholic or nonalcoholic fatty liver disease. Pacritinib significantly reduced liver fibrosis assessed by gene expression and Sirius red staining, as well as HSC activation assessed by alpha‐smooth muscle actin immunostaining in fibrotic mice. Furthermore, pacritinib decreased the gene expression of hepatic steatosis markers in experimental alcoholic liver disease. Additionally, pacritinib protected against liver injury as assessed by aminotransferase levels. Conclusions: This study demonstrates that the JAK2 inhibitor pacritinib may be promising for the treatment of alcoholic and nonalcoholic liver fibrosis and may be therefore relevant for human pathology.
Reinforced Hyaluronic Acid‐Based Matrices Promote 3D Neuronal Network Formation
Authors: Dieter Janzen, Ezgi Bakirci, Jessica Faber, Mateo Andrade Mier, Julia Hauptstein, Arindam Pal, Leonard Forster, Jonas Hazur, Aldo R. Boccaccini, Rainer Detsch, Jörg Teßmar, Silvia Budday, Torsten Blunk, Paul D. Dalton, Carmen Villmann
Journal: Advanced Healthcare Materials (2022)

3D neuronal cultures attempt to better replicate the in vivo environment to study neurological/neurodegenerative diseases compared to 2D models. A challenge to establish 3D neuron culture models is the low elastic modulus (30-500 Pa) of the native brain. Here, an ultra-soft matrix based on thiolated hyaluronic acid (HA-SH) reinforced with a microfiber frame is formulated and used. Hyaluronic acid represents an essential component of the brain extracellular matrix (ECM). Box-shaped frames with a microfiber spacing of 200 µm composed of 10-layers of poly(ɛ-caprolactone) (PCL) microfibers (9.7 ± 0.2 µm) made via melt electrowriting (MEW) are used to reinforce the HA-SH matrix which has an elastic modulus of 95 Pa. The neuronal viability is low in pure HA-SH matrix, however, when astrocytes are pre-seeded below this reinforced construct, they significantly support neuronal survival, network formation quantified by neurite length, and neuronal firing shown by Ca
Novel Aspects of Leukemia Pharmacogenomics
Authors: Deyanira Escalante-Bautista, Rosas-Vargas Haydeé, Doris Cerecedo
Journal: Leukemia (2022)

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children between the ages of 2 and 6. It is more frequent in boys than in girls. Currently, the overall cure rate of childhood ALL is approximately 75–80%. Integrated genomic analyses of patients with ALL have advanced the knowledge of the biological basis of ALL and have contributed to identifying subtypes, dysregulated pathways, and therapeutic targets that have resulted in the assignment of stratification categories and improvement of treatment strategies. Genomic studies in pediatric ALL patients have demonstrated chromosomal alterations during the evolution of the disease that directly influence the response to treatment and prognosis. Hence, the proper stratification of patients for identifying risks to prescribe the best treatment is crucial in the management of patients with ALL. Current risk stratification and treatment algorithms include cytogenetic alterations, clinical parameters, and levels of minimal residual disease. All these features are integrated to establish the clinical management of patients with ALL for surveillance of treatment success or for the identification of alternative therapeutic approaches. This chapter focuses on the genetic variations that affect the response to most of the chemotherapy drugs used for ALL.
Flow Cytometry in the Diagnosis of Leukemias
Authors: Weijie Li
Journal: Leukemia (2022)

Leukemia is a group of hematologic malignancies characterized by the proliferation of abnormal lymphoid or hematopoietic cells in the bone marrow and frequent involvement of peripheral blood and other organs. Leukemia can be classified as acute or chronic based on its rate of progression and specified as one of the many subtypes with other information incorporated according to the WHO classification. Common leukemias include acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. With the tremendous improvement in instrumentation and reagents during the past several decades, flow cytometry has become a powerful immunophenotyping tool, and plays a critically important role in the diagnosis of various leukemias. Flow cytometry can quickly identify the abnormal cell population, characterize its phenotype, give lineage classification, make the diagnosis, or narrow down the differential list. It can also assess the clonality of a mature B-cell or T-cell population, and determine DNA ploidy, which is also very useful for making diagnosis or predicting prognosis. Correlation with morphology, clinical information, and sometimes cytogenetic/molecular findings is always necessary for accurate interpretation of flow cytometry results. This chapter provides an overview of the principles and the significant roles of flow cytometry in the diagnosis of leukemias.
Of Science, Humanism, and Medicine
Journal: JAMA (2015)

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